A. Field of the Invention
The invention generally relates to a therapeutic composition of matter and method for administering said composition to human beings. Particularly, the several embodiments of the invention provide for treatment of renal disorders, such as uremia, for treatment of hepatic diseases, such as hyperammonemia and portal-systemic encephalopathy, for alleviating the effects of protein wastage and, in certain embodiments thereof, for altering metabolic pathways in order to prevent leakage of nitrogen from the body's metabolic pool.
B. Description of the Prior Art
Prior art treatment of the several bodily disorders to which the present invention finds application varies according to the particular disorder, this variation resulting in certain instances from a lack of understanding of the metabolic processes involved in the respective situations. Other than dialysis, prior art treatments applicable to renal disorders, such as uremia, center around replacement of amino acids lacking in the individual suffering from said disorder. In such a situation, nitrogenous wastes resulting from the normal breakdown of amino acids in the body are not adequately excreted and accumulate in the blood. Due to the inability to excrete these wastes, ingestion of protein must be restricted, thereby resulting in amino acid deficiencies. One particular treatment disclosed by Howe et al. in U.S. Pat. No. 2,457,820 provides for administering certain essential amino acids to correct this protein deficiency without overburdening the remaining kidney function.
Bergstrom et al. in U.S. Pat. No. 3,764,703 discloses a mixture of eight essential amino acids optionally combined with either or both L-arginine and L-histidine (which the patent calls "semi-essential" amino acids) for treatment of uremic conditions caused by renal insufficiency. However, the provision of additional amino acids in the blood stream often results in overburdenment of the kidney function, especially in severe cases, due to the resulting breakdown of the introduced amino acids into excessive nitrogenous wastes. Furthermore, these compounds are highly unpleasant to taste. For a comparison of results of essential amino acid therapy as opposed to that employing essentially the compositions of the present invention, see Walser et al. (1973), Journal of Clinical Investigation, 52:679. Also, Walser, M., (1975) "Keto-acids in the Treatment of Uremia", Clinical Nephrology, 3:80.
Other workers studying renal failure have suggested the dietary use of keto-acid analogs of amino acids and have proposed but have not demonstrated the use of keto-analogs of a combination of certain essential amino acids as a therapeutically beneficial treatment for uremia. These prior suggestions have been based on the assumption that such keto-acid analogs might combine with ammonia derived from urea breakdown in the intestines. Subsequently, such suggestions relating to keto-acid usage have been discounted. See editorial in The Lancet, Aug. 2, 1975, page 214. The present invention reveals that urea breakdown, and thus a high blood urea concentration, is not a prerequisite to efficacy of these analogs. On the contrary, low blood urea levels facilitate efficacy and can be maintained for months despite severe renal insufficiency.
The work resulting in the present invention has demonstrated the value of the use of combinations of hydroxy-acid analogs and keto-acid analogs of amino acids as a medicinal treatment for these disorders. The use of these combinations according to the invention diverts nitrogen away from urea formation, this nitrogen now being known to derive from body metabolic processes themselves. Thus, a particular object of the invention is to suppress urea formation and, in so doing, to minimize urea accumulation in body fluids, as well as nitrogen loss in the urine as urea.
Prior art treatment of hepatic failure such as is characterized by hyperammonemia and portal-systemic encaphalopathy is generally based on attempts to reduce the production of ammonia in the intestines and to restrict dietary protein. Individuals suffering from the aforementioned disorders are commonly deficient in protein owing to their intolerance of dietary protein; therefore, treatment according to the present invention provides for the reduction of ammonia in the bloodstream while simultaneously promoting protein synthesis.
Protein depletion due to dietary deficiency or excessive nitrogen losses may be treated by introduction of adequate protein to the diet. The present invention may also be used, and often with greater efficacy, to reduce protein requirements by diverting nitrogenous precursors in the body away from urea formation (urea is normally excreted, resulting in bodily nitrogen loss). This nitrogenous precursor diversion results in essential amino acid formation in the body by combination of the precursors not only with the keto-acids of the present combination but also the keto-acids formed by bodily enzymatic activity on the hydroxy-acid analogs in the combinations which are introduced into the body. The body's mechanisms for conserving protein can also be altered by administration of these combinations of hydroxy-acid analogs and keto-acid analogs of these amino acids. Thus, losses of nitrogen from the body can be diminished whether caused by malnutrition, cancer, diabetes, surgery, or any other wasting disease or condition which caused loss of body tissues. A positive nitrogen balance may be attained according to the invention by oral or parenteral administration of the present compositions of matter to reduce nitrogen wastage from the body.